Evidence from our center suggests that a functional polymorphism of the mu-opioid receptor (OPRM1) may be associated with clinical response to the opioid antagonist, naltrexone (NTX) in the treatment of alcohol dependence. The polymorphism is a single nucleotide polymorphism (SNP) in exon 1 (Asn40Asp). The SNP is found almost exclusively in individuals of European or Asian descent and has been demonstrated in vitro and in vivo to alter the function of the receptor. In retrospective analyses of patients adherent to NTX, persons with one or two copies of the Asp40 variant had a 73.9 % response (no relapse to alcohol use);whereas subjects homozygous for the Asn40 allele only had a 49.0 % positive response rate to treatment (p=0.040). In patients receiving placebo there was no association between response and genotype. This finding was recently confirmed in preliminary retrospective analysis of the COMBINE study with a 87% response in patients with the Asp40 allele who completed the trial. While certainly not definitive, these data suggest the potential for a genotype by treatment interaction that could better define treatment algorithms and dispel the belief that addiction is not a disease. In discussions with the FDA, a prospective randomized placebo controlled trial is required to consider labeling changes or approval of a biomarker. The primary aim of this proposal is to examine the interaction between the Asp40 allele variant and opioid receptor antagonism. We propose a prospective, 12-week, double-blind randomized trial of NTX and placebo among alcohol dependent patients with one or two copies of the Asp40 polymorphism compared to those homozygous for the Asn40 allele. Subjects will be randomized to medication based on genotype (2X2 cell design). The primary outcome will be treatment response. Results confirming the association with clinical response may significantly advance the use of NTX and will lead to a better understanding of the pathophysiology of alcohol dependence. The prospective design and inclusion of genotyping of all subjects will allow secondary hypotheses to be tested for other possible candidate genes and the acquired sample will facilitate whole genome associate studies of treatment response in a well characterized sample using a pharmacological probe of the reward system.